Age-related macular degeneration (AMD) is the most common cause of blindness in people over 65 years in many developed countries. It is known that the underlying causes of this disease are the functional decline and age-related atrophy of the retinal pigment epithelium (RPE). The RPE plays a crucial role in the maintenance of homeostasis and physiological functioning of the retina, while playing a key role in visual function. AMD is also thought to be caused by abnormalities resulting from age-related changes to Bruch's membrane, which functions as the basement membrane of the RPE, as well as the degeneration of the choriocapillaris, which supplies nutrients and oxygen to photoreceptor cells located in the outermost layer of the RPE and the neural retina, wherein phototransduction occurs.
Due to such changes, age-related macular degeneration is phenotypically divided into two subtypes: dry AMD, which is characterized by the degeneration and functional decline of the RPE, Bruch's membrane and the choriocapillaris; and wet AMD, which involves choroidal neovascularization (CNV) in addition to the aspects of dry AMD.
Dry AMD is characterized by the occurrence of drusen, in which complement system proteins and apolipoproteins accumulate between the RPE and the choriocapillaris. Perhaps the presence of drusen interferes with the movement of oxygen and nutrients in the choriocapillaris, and the occurrence of drusen itself reflects a decline in RPE cell function, eventually leading to oxygen deficiency, obstruction of mass transfer, and inflammation due to the death of RPE cells. Thus, dry AMD is characterized by geographic atrophy (GA), which results in extensive defects to RPE tissue over time.
Thus far, no therapeutics have been developed for dry AMD, though it is possible to delay its progression of somewhat via health foods containing vitamins, trace elements, and lutein, an antioxidant. Recently, various clinical studies targeting complement system-related proteins have been conducted, but studies targeting C3, C5, among others, have failed in developing an acceptable therapeutic. Lampalizumab (developed by Roche), a monoclonal antibody developed for factor blockade, was observed for 18 months in a phase II clinical trial, and showed the ability to inhibit GA enlargement by 20% when injected intravitreally once a month. It is currently undergoing phase III studies.
Wet AMD occurs in 5-10% of patients with dry AMD, and exhibits an acute phenotype that can cause blindness within a few months if left untreated, unlike dry AMD where the deterioration of vision progresses over a period of several years or even decades. In this case, a wide range of oxygen partial pressure reduction and nutrient decline across the subretinal space and the sub-RPE space, that is, tissue ischemia and the accompanying inflammatory response, play an important role. Oxidative stress and complement systems also act on wet AMD, with the latter playing an important role in immunological mechanisms, and choroidal neovascularization (CNV) characteristically occurs in the subretinal space or the sub-RPE space, resulting in serous fluid leakage and bleeding.
Choroidal neovascularization is known to be generated by endothelial cells, RPE cells, and inflammatory cells, such as monocytes and macrophages. Treatment of wet AMD utilizes anti-VEGF antibodies, whose use began around 2005, and has been shown to reduce blindness in many patients. The reason for the use of such agents is because it is known that VEGF plays a major role in the development of choroidal neovascularization. However, the use of anti-VEGF antibodies does not completely inhibit the formation and growth of choroidal neovascularization lesions, and photoreceptor cells in the macula which is the central part of the retina where choroidal neovascularization develops, eventually lose their function due to disintegration of the underlying RPE tissue. In addition, even when anti-VEGF antibodies are used, they act only on endothelial cells on the surface of the choroidal neovascularization lesions, and hence the size of choroidal neovascularization lesions continues to increase rather than decrease.
As such, it is necessary to develop drugs that target pathways other than the VEGF pathway involved in the development of choroidal neovascularization. Recently, Novartis has developed a drug having anti-PDGF effects, which serves to enhance the effects of drugs by separating pericytes, which are thought to be a major cause preventing anti-VEGF antibodies from effectively acting on vascular endothelial cells, from endothelial cells of choroidal neovascularization, easing the binding of anti-VEGF antibodies to the endothelial cells.
On the other hand, mTOR (mammalian target of rapamycin) plays an important role in cell proliferation and autophagy, and is considered a potential target in the treatment of malignant tumors. Thus, the development of therapeutic agents targeting mTOR has been conducted by many researchers. These therapeutic agents are mainly used for the purpose of inhibiting the action of mTOR to inhibit cell proliferation and activate autophagy.
Accordingly, the present inventors have made extensive efforts to develop a therapeutic with a novel target and mechanistically separate from the anti-VEGF antibodies currently used to treat macular degeneration, and as a result, have found that when a macular degeneration model elicited via laser-induced choroidal neovascularization is treated with an mTOR inhibitor, the lesion size of macular degeneration is reduced, thereby completing the present invention.